Development of Hsp90 inhibitor to regulate cytokine storms in excessive delayed- and acute inflammation.

Autor: Sim HB; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Sang Son J; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Gupta SK; College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea., Jeong SH; Department of Pharmacy, College of Pharmacy, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Choi YJ; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Han JY; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Ramos SC; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Kim H; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Park DH; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Yoo HJ; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Yoo YJ; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Chang DJ; Department of Pharmacy, College of Pharmacy, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea., Mun SK; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea. Electronic address: motomoto1210@naver.com., Seo YH; College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea. Electronic address: seoyho@kmu.ac.kr., Kim JJ; Department of Biomedical Science, Sunchon National University, 255 Jungang-Ro, Suncheon 57922, Republic of Korea. Electronic address: kimjj@scnu.ac.kr.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Aug 20; Vol. 137, pp. 112470. Date of Electronic Publication: 2024 Jun 21.
DOI: 10.1016/j.intimp.2024.112470
Abstrakt: Background: The surplus cytokines remaining after use in the early stages of the inflammatory response stimulate immune cells even after the response is over, causing a secondary inflammatory response and ultimately damaging the host, which is called a cytokine storm. Inhibiting heat shock protein 90 (Hsp90), which has recently been shown to play an important role in regulating inflammation in various cell types, may help control excessive inflammatory responses and cytokine storms.
Methods: We discovered an anti-inflammatory compound by measuring the inhibitory effect of CD86 expression on spleen DCs (sDCs) using the chemical compounds library of Hsp90 inhibitors. Subsequently, to select the hit compound, the production of cytokines and expression of surface molecules were measured on the bone marrow-derived DCs (BMDCs) and peritoneal macrophages. Then, we analyzed the response of antigen-specific Th1 cells. Finally, we confirmed the effect of the compound using acute lung injury (ALI) and delayed-type hypersensitivity (DTH) models.
Results: We identified Be01 as the hit compound, which reduced CD86 expression the most in sDCs. Treatment with Be01 decreased the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in BMDC and peritoneal macrophages stimulated by LPS. Under the DTH model, Be01 treatment reduced ear swelling and pro-inflammatory cytokines in the spleen. Similarly, Be01 treatment in the ALI model decreased neutrophil infiltration and lower levels of secreted cytokines (IL-6, TNF-α).
Conclusions: Reduction of CD80 and CD86 expression on DCs by Be01 indicates reduced secondary inflammatory response by Th1 cells, and reduced release of pro-inflammatory cytokines by peritoneal macrophages may initially control the cytokine storm.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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